The Dual Immunoregulatory Role of Creb3l1 Underlying Latent and Severe Tuberculosis Clinical Manifestation

During tuberculosis (TB), organ-specific immune responses and intracellular pathways play critical roles in disease progression and prognosis. Identifying genes that regulate these immune mechanisms remains a key challenge in improving TB management strategies. To investigate genes potentially associated with enhanced resistance to TB and the modulation of immune responses, we analyzed RNA-seq data from whole cells isolated from the lungs and livers of mice infected with Mycobacterium tuberculosis (Mtb). We hypothesized that these two organs mount distinct responses to infection, supported by differences in the immune response and bacterial burden kinetics observed in each tissue. Our analysis revealed differential gene expression profiles between the lungs and livers, primarily involving metabolic and immune-related pathways. Through meta-analysis, we identified orthologous genes shared between Mtb infected mice and human patients with latent pulmonary TB. In this omics analysis, the four genes, Creb3l1, Myo7b, Cyyr1, and Cbs, were differentially expressed and associated with either resistance or susceptibility. In vitro assays further demonstrated that knockdown of Creb3l1 in Mtb infected monocytes impaired key effector functions, including phagocytosis, bacterial killing, and apoptosis. These findings suggest that Creb3l1 contributes to bacterial containment in the lungs and may play a protective role during infection. Notably, Creb3l1 expression was also elevated in the peripheral blood of patients with severe TB, and correlated with increased levels of pro-inflammatory cytokines such as IL-17, IL-2, and IFN-γ. This pattern points to a potential dual role for Creb3l1 in TB. Under controlled conditions, such as latent infection, it may help regulate pulmonary inflammation, whereas during active disease, the expression is elevated in circulating leukocytes and associated with heightened cytokine production, which may reflect an immune attempt to counteract progressive infection.